Process for preparing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxylic acid

ABSTRACT

Starting from ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxo-propanoate (1), the present invention provides highly pure 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (5) in one-pot four steps using a single solvent.

TECHNICAL FIELD

The present invention relates to a novel process for preparing7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4dihydro-1,8-naphthyridine-3-carboxylicacid. Starting from ethyl3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxo-propanoate (1), the presentinvention provides highly pure7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (5)using single solvent in one-pot manner as shown in Scheme 1.

in which

Y represents straight-chain, branched, or cyclic alkyl, having 1 to 5carbon atoms, and unsubstituted or substituted by halogen, or representsphenyl unsubstituted or substituted by halogen.

BACKGROUND ART

Efficient preparation of compound (5) of the above Reaction Scheme 1 iscritical for an economical production of a fluoroquinolone-basedantibiotic used for the treatment of microbial infection. A priorprocess known in JP Laid-Open Hei 3-74231 prepares compound (5) throughthe following three steps:

Step 1: 3-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-oxopropanoic acid ethylester is reacted with triethyl orthoformate and acetic anhydride toprepare 2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxy acrylicacid ethyl ester;

Step 2: thus obtained compound is reacted with cyclopropylamine, and

Step 3: the resulting cyclopropyl enamine is cyclized by sodium hydrideto prepare naphthyridine ester.

However, in this process, the intermediates are separated at each step,and so the whole operation is complicated and resulted in low yield.

Another process to prepare compound (5) has been described in JPLaid-Open 2002-155081. This process improves the above process describedin JP Laid-Open Hei 3-74231 which is carried out the above steps 1 to 3in the same solvent without any intermediate isolation process. Thisinvention may be illustrated in more detail in the following threesteps:

Step 1: Compound (1) is reacted with triethyl orthoformate by heating inthe presence of acetic anhydride with concomitant removal of theby-products, ethanol and acetic acid. After the completion of thereaction, the residual triethyl orthoformate should be completelydistilled off under reduced pressure to prevent the formation of sideproduct in the next step.

Step 2: Thus obtained residue is cooled and dissolved in toluene. Tothis solution is added dropwise cyclopropylamine to prepare the enaminecompound.

Step 3: Finally, a catalytic amount of tetrabutylammonium bromide isadded to the solution of the enamine compound, and then aqueous sodiumhydroxide solution is added to cyclize. The crystallized naphthyridine3-carboxylic ester is filtered, washed, and dried and subsequentlyhydrolyzed to give compound (5) in the overall yield of about 85%.

This process is advantageous in preparing the naphthyridine esterwithout intermediates isolation, but also has the followingdisadvantage.

The reaction of Step 1 is already known in a number of references, andis a widely used as a general method (cf: WO 89/06649, EP 0 160 578 A1).However, this step has a couple of problems in an industrial aspect.First, after completion of the reaction, triethyl orthobromate should beremoved thoroughly through distillation under reduced pressure. Thisprocess takes a long time. Second, if the triethyl orthoformate is notcompletely removed, the residual triethyl orthoformate reacts withcyclopropylamine introduced in the next step to form by-products that isdifficult to purify.

DISCLOSURE OF THE INVENTION

The present inventors have conducted extensive studies to solve theproblems in the above JP Laid-Open 2002-155081. As a result, we havefound out that the object compound of the present invention,1,8-naphthyridine-3-carboxylic acid derivative, can be prepared in highyield and purity in a short cycle time without any need to conductcomplicated operations simply using dimethylformamide dialkylacetalinstead of triethyl orthoformate at the first step. Accordingly, thepreparation of intermediates of (2), (3)and (4)is proceeded in one-potmanner using the same solvent without any intermediate isolationprocess.

Below, the present invention is illustrated in more detail.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention relates to a process for preparing1,8-naphthyridine-3-carboxylic acid derivative of the following formula(5) featuring one-pot operation using a single solvent without anyintermediate isolation:

a) in the first step, the compound of the following formula (1)

is reacted with dimethylformamide dialkylacetal of formula Me₂NCH(OR)₂(wherein R represents straight-chain, branched or cyclic alkyl having 1to 9 carbon atoms, or benzyl) in a solvent in the presence of acidcatalyst to prepare the compound of the following formula (2),

b) in the second step, the resulting compound of the following formula(2)

is reacted with amine of formula YNH₂ prepare the compound of thefollowing formula (3),

in which

Y represents straight-chain, branched or cyclic alkyl, having 1 to 5carbon atoms and unsubstituted or substituted by halogen, or phenylunsubstituted or substituted by halogen,

c) in the third step, the resulting compound of the following formula(3),

in which

Y is as defined above,

is cyclized in the presence of quaternary ammonium salt and a base toprepare 1,8-naphthyridine-3-carboxylic acid ester of the followingformula (4),

in which

Y is as defined above, and

d) in the fourth step, the resulting compound of the following formula(4),

in which

Y is as defined above,

is hydrolyzed in the presence of acid to prepare1,8-naphthyridine-3-carboxylic acid derivative of the following formula(5),

in which

Y is as defined above.

Each step above is illustrated in more detail as follows.

Process a)

First, the solvent used in the processes a) to d) is halogenated alkaneor aromatic hydrocarbon solvent. The examples of halogenated alkanesolvents are methylene chloride, 1,2-dichloroethane, etc. The examplesof aromatic hydrocarbon solvents are benzene, chlorobenzene,1,2-dichlorobenzene, toluene, xylene, etc., preferably1,2-dichlorobenzene or toluene. The solvent is used in the amount of 3to 15 times (v/w), preferably 4 to 10 times (v/w), and more preferably 6times (v/w) with respect to the compound (1).

The specific examples of R in dimethylformamide dialkylacetal[Me₂NCH(OR)₂] used as a reaction substance are methyl, ethyl, propyl,isopropyl, butyl, t-butyl, neopentyl, benzyl, cyclohexyl, etc.,preferably methyl, ethyl, isopropyl, etc., and more preferably methyl.Dimethylformamide dialkylacetal is used in 1 to 3 mole equivalents,preferably 1 to 1.5 mole equivalents, and more preferably 1.05 to 1.15mole equivalents per mole of the compound (1).

The examples of acid catalyst are organic carboxylic acids such asacetic, propionic, and butanoic acid, etc., preferably acetic acid.Among these, acetic acid is used in the amount of 0.05 to 0.6 moleequivalents, preferably 0.1 to 0.4 mole equivalents, more preferably 0.2to 0.3 mole equivalents, per mole of the compound (1).

In the process a), the compound (1), dimethylformamide dialkylacetal,acid catalyst, and solvent may be combined in any order for theconvenience of process because the combining order does not affect thereaction. The reaction temperature is between 0 and 50° C., preferablybetween 10° C. and 40° C., and more preferably between 20° C. and 30° C.

More specifically, the process a) according to the present invention ismost preferably carried out by reacting compound (1)with 1.05 to 1.15mole equivalents of dimethylformamide dimethylacetal and 0.2 to 0.3 moleequivalents of acetic acid in 6 times (v/w) of toluene with respect tocompound (1)at 20° C. to 30° C.

Enamine structure shown in the compound (2) formed through process a)may be present in the mixture of E/Z form, and the present inventionincludes both forms.

Process b)

Amine of formula YNH₂ is added to the crude reaction mixture of compound(2) prepared according to process a). Here, specific examples of Y aresuch substituted or unsubstituted alkyl as methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, t-butyl, pentyl, etc. Among these,straight-chain or branched alkyl having 1 to 4 carbons are preferred,and methyl, ethyl, and propyl are more preferred. In the case ofhalogen-substituted alkyl group, fluorine, chlorine, bromine, iodine,etc. may be incorporated as a halogen moiety, and among these, fluorineand chlorine are preferred. Specific examples of halogen-substitutedalkyl group are chloromethyl, 2-chloroethyl, fluoromethyl,1-fluoroethyl, 2-fluoroethyl, etc., among which fluoromethyl and2-fluoroethyl are preferred. As examples of cyclic alkyl, there arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. These cyclicalkyls may be substituted with halogen such as fluorine, chlorine,bromine, and iodine, preferably chlorine and fluorine, in any position.As preferable examples of cyclic alkyl, 2-fluorocyclopropyl,2,2-difluorocyclopropyl, 2-chloro-2-fluorocyclopropyl, etc. may bementioned, and as more preferable examples of cyclic alkyl, there arecyclopropyl or 2-chloro-2-fluorocyclopropyl, etc. Furthermore, specificexamples of phenyl unsubstituted or substituted with halogen are phenyl,and 2,4-difluorophenyl, preferably 2,4-dufluorophenyl. In the presentinvention, cyclopropyl is most preferred.

In preparing the compound of formula (3) by using the above amine, amineof formula YNH₂ is used by 0.9 to 2 mole equivalents, preferably 1.0 to1.5 mole equivalents, more preferably 1.1 to 1.3 mole equivalents, mostpreferably 1.1 to 1.2 mole equivalents, per mole of the compound (1). Inthis reaction, for the convenience of stirred mixing, same solvent maybe added to the reaction solution through the whole steps, and theamount of solvent is 0 to 5 times (v/w) to the compound (1), but it ismost advantageous not to add solvent in view of reaction speed andreaction volume. Here, the reaction temperature is between 0 and 50° C.,preferably between 10° C. and 40° C., and more preferably between 20° C.and 30° C.

The solution containing the compound of formula (3) obtained in theabove reaction includes alcohol formed as by-products, residualunreacted YNH₂, and dimethylamine liberated from the compound of formula(2). Thus, it is preferred that these by-products and unreactedsubstances be removed. In that context, washing with a diluted aqueousacid solution is employed to lead to the removal of amine derivatives astheir salts form into the aqueous layer. The aqueous acid solution usedtherein may be prepared from inorganic acid such as diluted sulfuricacid, diluted hydrochloric acid, diluted phosphoric acid, or potassiumhydrogen sulfate, etc., or organic acid such as tartaric acid, citricacid, etc. The pH during the washing is 1 to 6, preferably 2 to 5, morepreferably 3 to 4. As an acid for washing, organic acids such astartaric acid, citric acid, etc. are more preferred. Among them, citricacid is the most preferred. When citric acid is used, a preferableconcentration of the aqueous solution is 3 to 30%, more preferably 5 to20%, and still more preferably 10 to 15%. The washing temperature isbetween 10° C. and 50° C., preferably between 25° C. and 45° C., andmore preferably between 30° C. and 40° C. The washing frequency may beone or several times, but if a preferable concentration of above citricacid is used at suitable temperature, one time of washing is sufficient.After layer separation, the separated organic layer may be washed onemore time with neutral water, if necessary.

Process c)

The crude compound (3) in the separated organic layer obtained in theprocess b) is cyclized in the presence of quaternary ammonium salt and abase to provide the compound of formula (4).

R in the quaternary ammonium salt (R₄NX) used in this process representsstraight-chian or branched alkyl having 1 to 18 carbons, or benzyl, etc;four Rs may be same or different; and X represents halogen, HSO₄ ⁻, orhydroxyl radical, wherein halogen is chlorine, bromine, iodine, etc. Asquaternary ammonium salt in this process c) according to the presentinvention, benzyltrialkylammonium salt, tetramethylammonium salt,tetraethylammonium salt, tetrabutylammonium salt, or the trade name“Aliquat 336,” “Adogen 464,” etc. may be generally used. Preferably,benzyltriethylammonium chloride; or bromide, or iodide, ortetraethylammonium chloride; or bromide or iodide, or tetrabutylammoniumchloride; or bromide or iodide is used. More preferably,tetrabutylammonium bromide is used. However, for convenience sake, anyof the above mentioned kinds of quaternary ammonium salt may be used.The quaternary ammonium salt may be used in the form of solid or aqueoussolution, and the used amount is 0.001 to 1 mole equivalents, preferably0.01 to 0.1 mole equivalents, more preferably 0.03 to 0.05 moleequivalents, per mole of the compound (1).

If X in the quaternary ammonium salt (R₄NX) used herein is halogen orHSO₄ ⁻, the use of base is essential, whereas when X is hydroxyl,quaternary ammonium salt itself functions as base, and so the use ofextra base is optional. The kinds of usable base are aqueous solutionsof lithium hydroxide, sodium hydroxide, potassium hydroxide, lithiumcarbonate, sodium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate, quaternary ammonium hydroxide, etc; preferablysodium hydroxide or potassium hydroxide. Among them, sodium hydroxide isthe most preferable. The used amount of base in this process is 0.9 to1.5 mole equivalents, preferably 1.0 to 1.3 mole equivalents, morepreferably 1.1 to 1.2 mole equivalents, per mole of compound (1).

On the other hand, aqueous quaternary ammonium hydroxide solution may beused instead of the mixture of quaternary ammonium salt and base, and inthis case, the aqueous quaternary ammonium hydroxide solution may beused in the amount of 0.9 to 1.5 mole equivalents, preferably 1.0 to 1.3mole equivalents, more preferably 1.05 to 1.15 mole equivalents, permole of compound (1). The reaction temperature is between 10 and 60° C.,preferably between 20 and 50° C., more preferably between 25 and 35° C.In conclusion, the cyclization of intermediate (3) to (4) isaccomplished in short time at ambient temperature to provide higherproductivity as well as purity with respect to the known arts.

Process d)

To the reaction mixture containing compound (4) prepared in process c)is added aqueous acid solution, and the mixture is heated for hydrolysisof the ester group, and the formed crystal is filtered to give compound(5).

The kind of acid used for hydrolysis is hydrochloric acid or sulfuricacid, preferably concentrated hydrochloric acid. The used amount is 1.5to 9 mole equivalents, preferably 3 to 6 mole equivalents, morepreferably 4 to 5 mole equivalents, per mole of compound (1). Inparticular, in case of using hydrochloric acid, 10 to 35% of aqueoushydrochloric acid solution may be used. It is preferred to use 35% ofaqueous hydrochloric acid solution.

The reaction may be carried out at a temperature between roomtemperature and 120° C., preferably 60° C. and 120° C., more preferably110° C. and 120° C. After the reaction is completed, the reactionsolution is cooled, the resulting solid is filtered, washed with waterand organic solvent, and the resulting filter cake is dried to givecompound (5) in high purity. The overall yield over four stps is usually90%or more.

As illustrated in the above description, the present invention has thefollowing advantages: the whole steps are carried out in one pot mannerwithout isolating the intermediates formed in each step and without anychange or addition of solvent. Since operations such as isolation,solvent exchange, reactor change, and reactor washing, etc. are notrequired, the present invention provides compound (5) in a highlyefficient and simple fashion in terms of cycle time of the process andthe yield and quality of the product.

The following examples are presented to illustrate further the presentinvention. However, it should be understood that these examples areintended to illustrate the present invention, and cannot limit the scopeof the present invention in any way.

EXAMPLE 1 Preparation of7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid [using tetrabutylammonium hydroxide]

To a stirred solution of 3-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-oxo-propanoic acid ethyl ester (compound (1): 10.0 g, 35.7 mmol) intoluene (60 ml) was added dimethyl-formamide dimethylacetal (4.68 g,39.3 mmol) and acetic acid (0.53 g, 8.9 mmol) at room temperature. Themixture was stirred at room temperature for 30 minutes. After3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxo-propanoic acid ethyl ester[compound (1)] was completely disappeared (monitored by HPLC),cyclopropylamine (2.24 g, 39.3 mmol) was added thereto, and the mixturewas stirred for 30 minutes. After compound (2) was completelydisappeared (monitored by HPLC), the reaction mixture was washed with10% aqueous citric acid solution. After layer separation, the separatedorganic layer was washed with distilled water, and 25% aqueoustetrabutylammonium hydroxide solution (40 g, 39.3 mmol) was added to thesolution. The resulting solution was stirred for 1 hour. After compound(3) was completely disappeared (monitored by HPLC), concentratedhydrochloric acid (14.7 ml, 146 mmol) was added to the reactionsolution, and the mixture was heated under reflux for 10 hours. Thereaction solution was cooled, filtered, washed with isopropanol,distilled water, and isopropanol in turn, and dried to give the titlecompound (5) (9.4 g) as a white crystal.

Total yield: 93.1%

Purity (HPLC): 98.6%.

EXAMPLE 2 Preparation of7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid [using tetrabutylammonium hydroxide andsodium hydroxide]

Starting from3-(2,6-Dichloro-5-fluoropyridin-3-yl)3 -oxo-propanoic acidethyl ester (compound (1): 10.0 g, 35.7 mmol)in toluene (70 ml),compound (3) was prepared according to the same procedure as Example 1.To the separated toluene solution of compound (3) was added distilledwater (10 ml) and then 40% aqueous tetrabutylammonium hydroxide solution(2.32 g, 3.57 mmol) and 10N sodium hydroxide (3.93 ml, 39.3 mmol) wereadded thereto to cyclize the reaction solution. After 1.3 hours,concentrated hydrochloric acid (16.7 ml) was added to the reactionsolution, and the mixture was heated under reflux for 8 hours tohydrolyze the mixture. The reaction solution was cooled, and theresulting solid was filtered, washed according to the same procedure asExample 1, and dried to give the title compound (5) (9.3 g) as a whitecrystal.

Total yield: 92.1%

Purity (HPLC): 99.9%.

EXAMPLE 3 Preparation of7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

To a stirred solution of 3-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-oxo-propanoic acid ethyl ester (compound (1): 85.0 kg, 303 mol) intoluene (808 kg)was added Me₂ NCH(OMe)₂ (40.8 kg ) and acetic acid (4.56kg). The mixture was stirred at room temperature for 50 minutes.Cyclopropylamine (22.53 kg) was added to the reaction mixture, and themixture was stirred at 25 to 35° C. for 50 minutes. The reaction mixturewas washed with 10% aqueous citric acid solution, and then water. Afterlayer separation, the aqueous layer was discarded, andtetrabutylammonium bromide (4.88 kg) and 25% aqueous sodium hydroxidesolution (53 kg) were added to the separated organic layer. Theresulting mixture was stirred for 2 hours. 35% aqueous hydrochloric acidsolution (142 kg) was added, and the resulting mixture was heated atreflux. After about 8 hours, the reaction mixture was cooled, and water(about 50 kg) was added thereto, and then the aqueous layer wasseparated off. The reaction solution was washed with water, and thesolid compound present in the separated organic layer was filtered, andwashed with isopropanol, water, and isopropanol in sequence. Theresulting solid was dried under vacuum to give the title compound (77kg) as a white crystal.

Total yield: 90%

Purity (HPLC): 99.9%.

1. A process for preparing 1,8-naphthyridine-3-carboxylic acid compoundof the following formula (5)

in which Y represents straight-chain, branched or cyclic alkyl, having 1to 5 carbon atoms, and unsubstituted or substituted by halogen, saidprocess comprising: the first step a) the compound of the followingformula (1),

is reacted with dimethylformamide dialkylacetal of formula Me₂NCH(OR)₂(wherein R represents straight-chain, branched or cyclic alkyl having 1to 9 carbon atoms, or represents benzyl) in a solvent in the presence ofacid catalyst to prepare the compound of the following formula (2),

the second step b) the resulting reaction mixture of the followingformula (2),

is reacted with amine of formula YNH₂ to prepare the compound of thefollowing formula (3),

in which Y is defined as above, the third step c) the resulting compoundof the following formula (3),

in which Y is as defined above, is cyclized in the presence ofquaternary ammonium salt and a base to prepare1,8-naphthyridine-3-carboxylic acid ester of the following formula (4),

in which Y is as defined above, and in the fourth step d) the resultingcompound of the following formula (4),

in which Y is as defined above, is hydrolyzed in the presence of an acidto prepare 1,8-naphthyridine-3-carboxylic acid compound of the saidformula (5), said process is characterized by a one pot operation of theabove steps using a single solvent system without intermediateisolation.
 2. The process according to claim 1 wherein R representsmethyl.
 3. The process according to claim 1 wherein the solvent used istoluene.
 4. The process according to claim 1 wherein dimethylformamidedialkylacetal of formula [Me₂NCH(OR)₂] is employed from 1.05 to 1.15mole equivalents per mole of the compound of formula (1).
 5. The processaccording to claim 1 wherein in the step a), acetic acid as acidcatalyst is employed from 0.2 to 0.3 mole equivalents per mole of thecompound of formula (1).
 6. The process according to claim 1 whereinamine of formula YNH₂ is cyclopropylamine.
 7. The process according toclaim 1 wherein amine of formula YNH₂ is employed from 1.1 to 1.2 moleequivalents per mole of the compound of formula (1).
 8. The processaccording to claim 1 wherein the reaction solution after the step b) iswashed with aqueous citric acid solution.
 9. The process according toclaim 1 wherein in the step c), aqueous tetrabutylammonium hydroxidesolution is used as base.
 10. The process according to claim 1 whereinin the step d), the reaction solution is heated under reflux by usingconcentrated aqueous hydrochloric acid.